Inter- and intramolecular alcohol additions to exo-glycals

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1 Pergamon Tetrahedron Letters (2002) TETRAHEDRN LETTERS Inter- and intramolecular alcohol additions to exo-glycals Chuan-Fa Chang, a, Wen-Bin Yang, c, * Che-Chien Chang and Chun-Hung Lin a,, * a Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan Institute of Biological Chemistry, Academia Sinica No. 128, Academia Road Section 2, Nan-Kang, Taipei 11529, Taiwan c Graduate Institute of Pharmacognosy Science, Taipei Medical University, Taipei, Taiwan Received 12 June 2002; revised 17 July 2002; accepted 18 July 2002 Astract Various exo-glycals were explored for the glycosidic ond formation and synthesis of spiroacetals in a stereoselective manner. The former reaction was an intermolecular alcohol addition to give the S new stereogenic center, resulting from the nucleophilic attack from the ottom face of the sugar ring. The latter one was carried out y the hydrooration of a sugar diene, followed y a susequent acid workup Elsevier Science Ltd. All rights reserved. endo-glycals (1,2-unsaturated sugars) have een well recognized as versatile uilding locks in the preparation of numerous iomolecules. For example, the glycal assemly method, developed y Danishefsky et al., has offered a novel and efficient strategy to synthesize Lewis and lood group determinants, gangliosides, and tumor-associated antigens. 1 7 endo-glycals are also chiral precursors for iologically interesting compounds such as staurosporine 8 and revetoxin B, 9 as well as sustrates for a variety of chemical transformations including azidonitration 10,11 and Michael addition to 2-nitrogalactal Therefore, it is reasonale that exoglycals can e widely utilized with the same great potential as endo-glycals. * Corresponding authors. Tel.: ; fax: ; [email protected] 1-exo-Methylene sugars, the simplest memers in the exo-glycal family, have een used as valuale glycosidase inhiitors, 15 and applied for the synthesis of C-glycosides. 16 However, the reactions of exo-glycals have not een investigated in detail, which is attriuted to no universal procedures of preparation. The reported syntheses of sustituted or specially functionalized exo-glycals usually require more laorious efforts, including Keck reaction of glycosyl dihalides, 17 Wittig olefination of sugar lactones, 18 Ramurg-Bäcklund rearrangement of S-glycosides, 19,20 and [2,]-Wittig sigmatropic rearrangement. 21 We recently presented a general method to synthesize exo-glycals y a nucleophilic addition of fully protected sugar lactones and the susequent dehydration. 22,2 The method is applicale to the gluco-, galacto-, and manno-type precursors, and stereoselective to give exclusively the (Z)-isomers of exo-glycals. 2 Herein we demonstrate inter- and intramolecular addition reactions of exo-glycals leading to a new stereocenter at the anomeric position. To uild up the chemistry with high stereoselectivity is indeed a synthetic challenge, the importance of which can e appreciated y the example as follows. Schmidt s group recently reported a novel and potent galactosyltransferase inhiitor ased on the design of disustrate analogue. 2 The synthesis took more than six reaction steps from fully protected galactonolactone to construct two tethers extending from the anomeric center. 2 exo-glycals were first explored for glycosidic ond formation. Sugar diene 1 was sujected to the addition of allyl alcohol in the presence of BF Et 2 to give a single product 2 in 51% yield (entry a of Tale 1). n the asis of NESY analysis, compound 2 was determined to have a C-sustituent on the -position and an -allyl group on the -position. 25 The reactivity was greatly improved as the ethylene sustituent was replaced with caroxyethyl ester (entry ). Tale 1 also demonstrated the Michael addition reactions to conjugated esters 5 to generate products 6 1, respectively. The reaction yields varied in different nucleophiles (e.g. entries f). Apparently the steric hindrance played the role here. When different types of exo-glycals were investigated (e.g. entries, g and i), the significant difference in reactivity was oserved. The exo-glycal of manno-type was more reactive than those of gluco- and galacto-types /02/$ - see front matter 2002 Elsevier Science Ltd. All rights reserved. PII: S000-09(02)017-9

2 6516 C.-F. Chang et al. / Tetrahedron Letters (2002) Tale 1. entry sustrate nucleophile time product yield a c 1 C 2 Et 6 1' 2 h S 51% 2 1" 12 h S 2 Et 92% RC 2 h 6 (R = allyl) 7 (R = ethyl) 89% d 16 h 8 (R = 1-utyl) 9% e 2 h 9 (R = enzyl) 78% f 2 h 10 (R = 2-propyl) 5% g C2 Et 6 h 1' C 2 Et 2 S R 11 (R = allyl) 98% h 10 h 12 (R = ethyl) 91% i 5 C 2 Et 12 h S C 2 Et R 1 (R = allyl) 95% j 5 H 16 h 1 (R = CH 2 CH 2 ) 99% a Reaction conditions: all the reactions were carried out at 25 o C in CH 2 Cl 2 in the presence of BF. Et 2 (5 eq) and A molecular seives. 10 equivalents of nucleophiles were added. In addition, all the reactions led to the same stereochemical outcome; i.e. the S-configuration was otained at the anomeric center of all the products. The stereochemistry was consistent with a nucleophilic attack from the ottom face of the sugar ring. All the product structures were supported y DEPT 26 and NESY spectra in addition to other spectroscopic properties. For instance, the NESY spectra of ester 11 indicated the cross peaks etween H1 (.22) and H2 (.); the ones etween H1 (.10) 27 andh5(.66). The data thus verify the -allyl group located at the -position. It is of interest that the spatial correlation always exists etween H-1 and H-5 among all the glycoside products, consistent with that etween H-1 and H-2. Furthermore, the addition reactions to exo-glycals were carried out intramolecularly y a uilt-in alcohol. In our previous work the hydrooration of exo-glycosyl diene 15 resulted in the formation of isomeric spiroacetals 16 under an acidic workup condition, as shown in Fig a The result was realized due to the selective functionalization of the terminal olefin and a susequent acid-catalyzed cyclization. 22a Further studies on various types of sugar dienes (Fig. 1) including gluco-, galacto-, manno-, and fuco-type precursors revealed several interesting features. Some of the glycosyl spiroacetals can e otained in a stereoselective manner. The hydrooration of dienes 17 19, quenched y oxidation with H 2 2 and camphor sulfonic acid (CSA), gave spiroacetals 22 2 as a single isomer, respectively. n the other hand, when dienes 20 and 21 were individually sujected to the same conditions, only moderate selectivity was oserved and pairs of separale isomers were otained in ratios of :1 (25/26) and 8:1 (27/28), respectively. A mixture of 25 and 26 (/1) were deprotected using TBAF and enzylated to give the known compounds 29 and 0 in the ratio of /1. 28 Upon treatment with trifluoroacetic acid (TFA), only the former product 29 was left as the thermodynamically favored isomer. The result was in accordance with the anomeric effect. Likewise, fully enzylated spiroacetals 1 and 2 (as a mixture of 8/1) can e derived from the mixture of 27 and 28 (8/1). Compound 2

3 C.-F. Chang et al. / Tetrahedron Letters (2002) assigned for spiro sugars 2, 2, 29 and 1 were also favored y the anomeric effect. During the formation of these spiro sugars, a homoallyl alcohol has een suggested to exist after the selective hydration of the terminal olefin, 22a which was followed y the acid-catalyzed cyclization. According to Baldwin s rule for the five-memered ring closure, however, 5-endo-trigonal annulation (Fig. 2) is not favored. An oxocarenium ion was thus proposed to e the plausile intermediate to qualify for the stereochemical requirement (5-exo-trigonal annulation) of Baldwin s ring forming processes. Interestingly, when 2 equiv. of orane were used in the hydrooration of diene 17, a C-glycosyl diol was produced (Fig. ). Further derivatization with p-romoenzoyl chloride gave compound as a crystalline product, suitale for single crystal X-ray analysis as shown in the RTEP drawing in Fig.. 0 Thus the new stereogenic centers were corroorated to exhiit the (1R, 1 R) chirality. The result can e rationalized that the steric hindrance owing to the C2 silyl group forced the syn addition of orane to occur in the top face of the sugar ring. As a consequence, it is possile to prepare C-glycosides y the hydrooration of exo-glycals with high stereoselectivity. In conclusion, exo-glycals were applied for the stereoselective alcohol additions to afford unusual glycosides with oth - and C-glycosidic linkages, as well as glycosyl spiroacetals. In addition to simple alcohols, we are currently utilizing sugars as nucleophiles to generate disaccharides or oligosaccharides, which will e reported in due course. Also it is of interest to investigate how various different factors affect the reactivity of exo-glycals, such as Lewis acid and sustituted functionality. Figure 1. Reagents and conditions: (a) BH THF; () H 2 2, CSA; (c) (i) TBAF; (ii) NaH, BnBr; (d) TFA. Supplementary material availale: 1 H and 1 C NMR spectra of compounds 2, 6 1, 22 25, 28 and NESY spectra of compounds 2, 6, 11, 12, 2 to indicate the correlation of H1 and H2 in space were all included. completely converted to the other more stale isomer 1 under the condition of TFA. The new stereogenic center of the spiro sugars was diagnosed y comparison with the reported NMR spectral data (e.g. compounds 29 and 0) 28 or NESY studies. For instance, the NESY spectra of spiroacetal 2 indicated the cross peaks etween H1 ( 1.95) and H2 (.0), which thus supported R-configuration at C1 position. 29 The stereochemical configurations Figure 2.

4 6518 C.-F. Chang et al. / Tetrahedron Letters (2002) Figure. Reagents and conditions: (a) BH THF (2 equiv.); () H 2 2, Na; (c) p-romoenzoyl chloride, pyridine. Acknowledgements The work is financially supported y National Science Council (NSC M ), National Health Research Institute (NSC B ), and Academia Sinica. We are grateful for the suggestion of one referee aout the ring closure ased on Baldwin s rule. References 1. Williams, L. J.; Garaccio, R. M.; Danishefsky, S. J. In Carohydrates in Chemistry and Biology; Ernst, B.; Hart, G. W.; Sinay, P., Eds.; Wiley-VCH Verlag GmH: Weinheim, Germany, 2000; Vol. 1, pp Seeerger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 1, Seeerger, P. H.; Beee, X.; Sukenick, G. D.; Pochapsky, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1997, 6, 91.. Zheng, C.; Seeerger, P. H.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1998, 7, Zheng, C.; Seeerger, P. H.; Danishefsky, S. J. J. rg. Chem. 1998, 6, Seeerger, P. H.; Eckhardt, M.; Gutteridge, C. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 5, (a) Link, J. T.; Gallant, M.; Huer, S.; Danishefsky, S. J. J. Am. Chem. Soc. 199, 115, 782; () Link, J. T.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 1995, 117, 552; (c) Link, J. T.; Raghavan, S.; Gallant, M.; Danishefsky, S. J.; Ballas, M. J. Am. Chem. Soc. 1995, 117, Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K. J. Chem. Soc., Chem. Commun. 1985, Lemieux, R. U.; Ratcliffe, R. M. Can. J. Chem. 1997, 57, Paulson, H. Angew. Chem., Int. Ed. Engl. 1982, 21, Winterfeld, G. A.; Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 2001, 0, Winterfeld, G. A.; Ito, Y.; gawa, T.; Schmidt, R. R. Eur. J. rg. Chem. 1999, Das, J.; Schmidt, R. R. Eur. J. rg. Chem. 1998, (a) Hehre, E. J.; Brewer, C. F.; Uchiyama, T.; Schlesselmann, P.; Lehmann, J. Biochemistry 1980, 19, 557; () Dettinger, H.-M.; Kurz, G.; Lehmann, J. Carohydr. Res. 1979, 7, 01; (c) Fritz, H.; Lehmann, J.; Schlesselmann, P. Carohydr. Res. 198, 11, 71; (d) Brewer, C. F.; Hehre, E. J.; Lehmann, J.; Weiser, W. Lieigs Ann. 198, 1078; (e) Vasella, A.; Witzig, C.; Waldraff, C.; Uhlmann, P.; Briner, K.; Bernet, B.; Panza, L.; Husi, R. Helv. Chim. Acta 199, 76, (a) Smoliakova, I. P. Curr. rg. Chem. 2000,, 589; () Belica, P. S.; Franck, R. W. Tetrahedron Lett. 1998, 9, 8225; (c) Lay, L.; Nicotra, F.; Panza, L.; Russo, G.; Caneva, E. J. rg. Chem. 1992, 57, (a) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G.; Raphoz, C. Tetrahedron Lett. 1997, 8, 8185; () Praly, J.-P.; Kharraf, Z. E.; Descotes, G. Carohydr. Res. 1992, 22, 117; (c) Praly, J.-P.; Chen, G.-R.; Gola, J.; Hetzer, G. Eur. J. rg. Chem. 2000, (a) Xie, J.; Molina, A.; Czernecki, S. J. Carohydr. Chem. 1999, 18, 81; () Molina, A.; Czernecki, S.; Xie, J. Tetrahedron Lett. 1998, 9, (a) Alcaraz, M.-L.; Griffin, F. K.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 9, 818; () Griffin, F. K.; Murphy, P. V.; Paterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 9, 8179; (c) For a detailed

5 C.-F. Chang et al. / Tetrahedron Letters (2002) review, see: Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 1999, (a) Belica, P. S.; Franck, R. W. Tetrahedron Lett. 1998, 9, 8225; () Pasetto, P.; Chen, X.; Drain, C. M.; Franck, R. W. Chem. Commun. 2001, 81; (c) Yang, G.; Franck, R. W.; Bittman, R.; Samadden, P.; Arthur, G. rg. Lett. 2001,, Lay, L.; Meldal, M.; Nicotra, F.; Panza, L.; Russo, G. J. Chem. Soc., Chem. Commun. 1997, (a) Yang, W.-B.; Chang, C.-F.; Wang, S.-H.; Teo, C.-F.; Lin, C.-H. Tetrahedron Lett. 2001, 2, 657; () Yang, W.-B.; Wu, C.-Y.; Chang, C.-C.; Wang, S.-H.; Teo, C.-F.; Lin, C.-H. Tetrahedron Lett. 2001, 2, Yang, W.-B.; Yang, Y.-Y.; Gu, Y.-F.; Wang, S.-H.; Chang, C.-C.; Lin, C.-H. J. rg. Chem. 2002, 67, Waldscheck, B.; Streiff, M.; Notz, W.; Kinzy, W.; Schmidt, R. R. Angew. Chem., Int. Ed. Engl. 2001, 0, The NESY spectra of glycoside 2 indicated the spatial correlation etween H1 ( 2.6) and H2 (.51), which thus verified the C-sustituent located at the -position. 26. The DEPT spectra of ester 11, for example, indicated C1 ( 101.2) to e a quartenary caron. 27. C1 is defined as the caron next to the glycosidic oxygen. 28. Martin, A.; Salazar, J. A.; Suarez, E. J. rg. Chem. 1996, 61, The NESY and NE experiments have een used for the characterization of similar molecules, see (a) Schweizer, F.; Inazu, T. rg. Lett. 2001,, 115; () Wardrop, D. J.; Zhang, W., Fritz, J. rg. Lett. 2002,, Crystallographic data of have een deposited with the Camridge Crystallographic Data Centre as the deposition numer CCDC Copies of the data can e otained, free of charge, on application to CCDC, 12 Union Road, Camridge, CB2 1EZ, UK (fax: +(0) or [email protected]).